Impairment of GABA‐mediated inhibition is one of the main hypotheses invoked to explain seizure activity, both in experimental models and in human epilepsy. We have studied the distribution and the neurochemical characteristics of certain GABAergic circuits in the normal and epileptic human sclerotic hippocampal formation. We have focused our attention mainly on chandelier cells because, together with basket cells, they are considered to have powerful effects on spike generation. Chandelier cells represent a unique type of interneuron whose axon terminals (Ch‐terminals) form synapses with the axon initial segments of cortical pyramidal cells and granular cells of the dentate gyrus. Different neurochemical subpopulations of chandelier cells have been identified by immunocytochemistry, mainly in the neocortex. Markers for Ch‐terminals include the GABA transporter 1 (GAT‐1), the polysialylated form of the cell‐surface glycoprotein neural cell adhesion molecule (PSA‐NCAM) and the calcium‐binding proteins parvalbumin (PV) and calbindin D‐28k (CB). In the normal hippocampal formation, GAT‐1‐ and PV‐immunoreactive (‐ir) Ch‐terminals were identified in the granular and polymorphic layers of the dentate gyrus, in the strata pyramidale and oriens of the CA fields, and in the pyramidal layer of the subicular complex. In addition, and in contrast to the hippocampus and dentate gyrus, subsets of Ch‐terminals in the upper pyramidal layer of the normal subiculum express CB and PSA‐NCAM. The sclerotic hippocampus of epileptic patients presented an impressive morphological and neurochemical reorganization of Ch‐terminals and basket formations. This was apparent in the dentate gyrus and hippocampal formation, but not in the subiculum, which appeared to remain unaltered. Principally, numerous and more complex PV‐ and CB‐ir Ch‐terminals, as well as dense PV‐ir basket formations, appeared in some hippocampal segments, whereas in other regions there was a lack of labelled elements. These changes varied considerably not only between different patients, but also within different hippocampal fields in a given patient. In general, the changes were not correlated with the clinical characteristics or degree of histopathological alterations observed in the patients, such as granular cell dispersion, neuron loss and proliferation of mossy fibres. However, some surviving neurons in the regions adjacent to the areas of neuron loss were consistently innervated by dense basket formations and complex Ch‐terminals. These results indicate that, in the human epileptic hippocampus, GABAergic circuits are more highly modified than previously thought. When considered along with other extrahippocampal alterations, we suggest that these changes are important in the pathophysiology of temporal lobe epilepsy associated with hippocampal sclerosis.

Immunocytochemical methods were used to study alterations in inhibitory neuronal circuits in human neocortex resected during surgical treatment of intractable temporal epilepsy associated or not with brain tumours. The epileptogenic cortex was characterized and divided into spiking or non-spiking zones by intraoperative electrocorticography (ECOG). The resected cortex was cut into blocks, sectioned and stained immunocytochemically for visualization of glutamic acid decarboxylase (GAD), the calcium-binding protein, parvalbumin (PV) and glial fibrillary acidic protein (GFAP). A variety of alterations in cortical neuronal circuits as revealed by immunocytochemical and histological methods were found. Similar alterations in inhibitory neuronal circuits appear to occur independently of the primary epileptogenic site and pathology associated with epilepsy, which suggests that there is possibly a common basic underlying mechanism that leads to seizure activity. These changes were apparently unrelated to ECOG findings at surgery, which bring into question the value of the use of interictal epileptic discharges recorded by ECOG to guide cortical resections. The most conspicuous and common change was the loss of chandelier cells. The finding that these cells are among the most vulnerable types of GABAergic interneurons in the epileptogenic temporal cortex indicates that they might be of great functional importance, since the axon terminals of chandelier cells are likely to exert powerful regulation of impulse generation in cortical pyramidal cells. Therefore, these cells might represent a key component in the aetiology of human epilepsy.

Focal cortical dysplasia (FCD) is a pathology that is characterized by the abnormal development of the neocortex. Indeed, a wide range of abnormalities in the cortical mantle have been associated with this pathology, including cytoarchitectonic alterations and the presence of dysmorphic neurons, balloon cells and ectopic neurons in the white matter. FCD is commonly associated with epilepsy, and hence we have studied the ultrastructure of cortical tissue resected from three subjects with intractable epilepsy secondary to cortical dysplasia to identify possible alterations in synaptic circuitry, using correlative light and electron microscopic methods. While the balloon cells found in this tissue do not appear to receive synaptic contacts, the ectopic neurons in the white matter were abnormally large and were surrounded by hypertrophic basket formations immunoreactive for the calcium-binding protein parvalbumin. Furthermore, these basket formations formed symmetrical (inhibitory) synapses with both the somata and the proximal portion of the dendrites of these giant ectopic neurons. A quantitative analysis revealed that in the dysplastic tissue, the density of excitatory and inhibitory synapses was different from that of the normal adjacent cortex. Both increases and decreases in synaptic density were observed, as well as changes in the proportion of excitatory and inhibitory synapses. However, we could not establish a common pattern of changes, either in the same patients or between different patients. These results suggest that cortical dysplasia leads to multiple changes in excitatory and inhibitory synaptic circuits. We discuss the possible relationship between these alterations and epilepsy, bearing in mind the possible limitations that preclude the extrapolation of the results to the whole population of epileptic patients with dysplastic neocortex.